EGFR-targeting RNase A-cetuximab antibody-drug conjugate induces ROS-mediated apoptosis to overcome drug resistance in KRAS mutant cancer cells
Abstract Antibody-drug conjugates (ADCs) are an emerging strategy in cancer therapy, enhancing precision and efficacy by linking targeted antibodies to potent cytotoxic agents. This study introduces a novel ADC that combines ribonuclease A (RNase A) with cetuximab (Cet), an anti-EGFR monoclonal anti...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-85856-9 |
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| author | Bita Jafary Mostafa Akbarzadeh-Khiavi Hamed Farzi-Khajeh Azam Safary Khosro Adibkia |
| author_facet | Bita Jafary Mostafa Akbarzadeh-Khiavi Hamed Farzi-Khajeh Azam Safary Khosro Adibkia |
| author_sort | Bita Jafary |
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| description | Abstract Antibody-drug conjugates (ADCs) are an emerging strategy in cancer therapy, enhancing precision and efficacy by linking targeted antibodies to potent cytotoxic agents. This study introduces a novel ADC that combines ribonuclease A (RNase A) with cetuximab (Cet), an anti-EGFR monoclonal antibody, through a polyethylene glycol (PEG) linker (RN-PEG-Cet), aimed to induce apoptosis in KRAS mutant colorectal cancer (CRC) via a ROS-mediated pathway. RN-PEG-Cet was successfully synthesized and characterized for its physicochemical properties, retaining full enzymatic activity in RNA degradation and high binding affinity to EGFR. In KRAS mutant SW-480 cells, RN-PEG-Cet significantly reduced cell viability at lower doses, with an IC50 of 11.7 µg/mL at 72 h. Compared to free Cet, RN-PEG-Cet demonstrated a ~ 2-fold increase in apoptosis and a ~ 3.5-fold increase in ROS production. The conjugate also disrupted the Nrf2/Keap1 pathway, with a significant upregulation of Keap1 (FC = 3.7, p ≤ 0.01) and downregulation of Nrf2 (FC = 3.3, p < 0.01), highlighting its role in impairing antioxidant defenses and promoting ROS-mediated cytotoxicity. These findings emphasize the potential of RN-PEG-Cet as a novel therapeutic approach for KRAS mutant CRC, offering superior apoptosis induction and targeted cytotoxicity compared to conventional therapies. This ADC could represent a new strategy for improving CRC treatment outcomes by effectively overcoming resistance mechanisms. |
| format | Article |
| id | doaj-art-c1e66f08128348de937d3c338a06173d |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-c1e66f08128348de937d3c338a06173d2025-01-12T12:16:29ZengNature PortfolioScientific Reports2045-23222025-01-0115111610.1038/s41598-025-85856-9EGFR-targeting RNase A-cetuximab antibody-drug conjugate induces ROS-mediated apoptosis to overcome drug resistance in KRAS mutant cancer cellsBita Jafary0Mostafa Akbarzadeh-Khiavi1Hamed Farzi-Khajeh2Azam Safary3Khosro Adibkia4Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical SciencesLiver and Gastrointestinal Diseases Research Center, Tabriz University of Medical SciencesLiver and Gastrointestinal Diseases Research Center, Tabriz University of Medical SciencesConnective Tissue Diseases Research Center, Tabriz University of Medical SciencesResearch Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical SciencesAbstract Antibody-drug conjugates (ADCs) are an emerging strategy in cancer therapy, enhancing precision and efficacy by linking targeted antibodies to potent cytotoxic agents. This study introduces a novel ADC that combines ribonuclease A (RNase A) with cetuximab (Cet), an anti-EGFR monoclonal antibody, through a polyethylene glycol (PEG) linker (RN-PEG-Cet), aimed to induce apoptosis in KRAS mutant colorectal cancer (CRC) via a ROS-mediated pathway. RN-PEG-Cet was successfully synthesized and characterized for its physicochemical properties, retaining full enzymatic activity in RNA degradation and high binding affinity to EGFR. In KRAS mutant SW-480 cells, RN-PEG-Cet significantly reduced cell viability at lower doses, with an IC50 of 11.7 µg/mL at 72 h. Compared to free Cet, RN-PEG-Cet demonstrated a ~ 2-fold increase in apoptosis and a ~ 3.5-fold increase in ROS production. The conjugate also disrupted the Nrf2/Keap1 pathway, with a significant upregulation of Keap1 (FC = 3.7, p ≤ 0.01) and downregulation of Nrf2 (FC = 3.3, p < 0.01), highlighting its role in impairing antioxidant defenses and promoting ROS-mediated cytotoxicity. These findings emphasize the potential of RN-PEG-Cet as a novel therapeutic approach for KRAS mutant CRC, offering superior apoptosis induction and targeted cytotoxicity compared to conventional therapies. This ADC could represent a new strategy for improving CRC treatment outcomes by effectively overcoming resistance mechanisms.https://doi.org/10.1038/s41598-025-85856-9Antibody-drug conjugates (ADCs)RNase ACetuximabReactive oxygen species (ROS)Epidermal growth factor receptor (EGFR)Colorectal cancer |
| spellingShingle | Bita Jafary Mostafa Akbarzadeh-Khiavi Hamed Farzi-Khajeh Azam Safary Khosro Adibkia EGFR-targeting RNase A-cetuximab antibody-drug conjugate induces ROS-mediated apoptosis to overcome drug resistance in KRAS mutant cancer cells Scientific Reports Antibody-drug conjugates (ADCs) RNase A Cetuximab Reactive oxygen species (ROS) Epidermal growth factor receptor (EGFR) Colorectal cancer |
| title | EGFR-targeting RNase A-cetuximab antibody-drug conjugate induces ROS-mediated apoptosis to overcome drug resistance in KRAS mutant cancer cells |
| title_full | EGFR-targeting RNase A-cetuximab antibody-drug conjugate induces ROS-mediated apoptosis to overcome drug resistance in KRAS mutant cancer cells |
| title_fullStr | EGFR-targeting RNase A-cetuximab antibody-drug conjugate induces ROS-mediated apoptosis to overcome drug resistance in KRAS mutant cancer cells |
| title_full_unstemmed | EGFR-targeting RNase A-cetuximab antibody-drug conjugate induces ROS-mediated apoptosis to overcome drug resistance in KRAS mutant cancer cells |
| title_short | EGFR-targeting RNase A-cetuximab antibody-drug conjugate induces ROS-mediated apoptosis to overcome drug resistance in KRAS mutant cancer cells |
| title_sort | egfr targeting rnase a cetuximab antibody drug conjugate induces ros mediated apoptosis to overcome drug resistance in kras mutant cancer cells |
| topic | Antibody-drug conjugates (ADCs) RNase A Cetuximab Reactive oxygen species (ROS) Epidermal growth factor receptor (EGFR) Colorectal cancer |
| url | https://doi.org/10.1038/s41598-025-85856-9 |
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